Psoriasis is a benign disease of human skin generally characterized by plaques covered by thickened scales. The disease is caused by increased proliferation of epidermal cells of unknown cause. In normal skin the time required for a cell to move from the basal layer to the upper granular layer is about five weeks. In psoriasis, this time is only 6 to 9 days, partially due to an increase in the number of proliferating cells and an increase in the proportion of cells which are dividing (G. Grove, Int. J. Dermatol. 18:111, 1979). Approximately 2% of the population the United States have psoriasis, occurring in about 3% of caucasian Americans, in about 1% of African Americans, and rarely in native Americans.
Epidermal hyperplasia associated with inflammation is characteristic of psoriatic skin. Skin biopsies of affected areas show hyperkeratosis with retention of nuclear fragments, increased proliferation with defective keratinization, and chronic inflammatory infiltrates. (E. A. Bauer, M. Tabas and J. B. Goslen, in Textbook of Internal Medicine, W. N. Kelly (ed.), 1989, pp 1042-1045). With increased cell proliferation, there is increased DNA synthesis in the affected tissue which has been the basis for assays for evaluating the efficacy of anti-psoriasis agents.
There is no true animal model for psoriasis although rare primates with clinical and histopathological features of psoriasis have been reported (N.J. Lowe, Drug Dev. Res. 13:147-155, 1988). Consequently, investigation of anti-psoriasis drugs has relied on experimentally-induced hyperplasia in animals or a mouse strain bearing the spontaneous mutation (fsn) for flaky skin (J. P. Sundberg et al., J. Invest. Dermatol. 92:414, 1989). Another mouse model having epidermal proliferation is the essential fatty-acid deficient (EFAD) hairless mouse.
Experimentally induced animal models also include athymic nude mice, which are immunologically defective, engrafted with diseased human skin.
Current therapies consist of efforts to reduce the rapid cell proliferation and to reduce inflammation. These therapies include use of active agents topically, systemically or both, which can be combined with irradiation. Topical treatments include use of steroid creams, and use of coal tar ointments followed by ultraviolet irradiation (UV B, 290-320 nm). Topical 5-fluorouracil has been used with some success but the treatment causes severe erythema, edema, bullae formation and ulceration of the skin in treated areas and therefore is not well accepted by patients (C. J. McDonald, Pharmac. Ther. 14:1-24, 1981). TRIAZURE.TM. (6-azauridine triacetate) has been tested topically on the skin of patients with psoriasis but was without effect (William Drell, personal communication, May, 1993).
Antiproliferative agents, including methotrexate, 6-azauridine and triazure, have also been used systemically. Extensive psoriasis has been treated with oral administration of 8-methoxypsoralen, a photosensitizer, followed by ultraviolet A (320 nm) irradiation or administration of retinoids, such as etretinate, followed by ultraviolet A irradiation (C. J. McDonald, Pharmac. Ther. 14:1-24, 1981; E. A. Bauer, M. Tabas, and J. B. Goslen, in Textbook of Internal Medicine, W. N. Kelly (ed.), 1989, pp 1042-1045).
Other diseases caused by hyperproliferation of skin cells include atopic dermatitis, lichen planus, actinic keratosis, basal cell carcinoma and squamous cell carcinoma. The topical use of phosphate esters of antiproliferative nucleosides and dideoxynucleosides and their analogs has not been reported for treating psoriasis or other diseases caused by hyperproliferation of skin cells.
Copending U.S. patent application (Ser. No. 08/060,258, hereby incorporated by reference) discloses that phosphate esters of antiherpes nucleosides, such as acyclovir, are effective in animals infected with mutant virus strains in which acyclovir cannot be converted to acyclovir phosphates due to a mutation affecting the vital enzyme, thymidine kinase.